1. Field of the Invention
This invention relates to methods for alleviating paroxysmal disorders in an animal. The invention particularly relates to relieving epilepsy, by modulating glycolysis in brain cells while maintaining the metabolic integrity thereof. The invention specifically relates to the use of antiglycolytic compounds such as 2-deoxy-D-glucose (2-DG) as anticonvulsant and antiepileptic agents for the treatment of seizures, epilepsy and other paroxysmal alterations in neurological and neuropsychiatric function, including pain and particularly neuropathic pain.
2. Background of the Invention
Functions of the central nervous system may be impaired by a variety of paroxysmal alterations including seizures, syncope, pain, migraine, and transient ischemia. The nerve cells of the brain function in a highly complex but organized manner. A sudden temporary interruption in some or all of the functions of the nerve cells results in a “seizure”. Each individual has a “seizure threshold” or level of resistance to seizures: this threshold varies from person to person, most likely due to their genetic makeup and other developmental factors (Stafstrom, 1998, Pediatrics in Review 19: 335-344).
A person with a tendency to have repeated seizures may be suffering from epilepsy. Epilepsy is a generic term for a common serious neurological condition that affects one in every 200 adults and one in every 100 children (Hauser & Hersdorffer, 1990, EPILEPSY: FREQUENCY, CAUSES AND CONSEQUENCES, New York: Demos). Epilepsy is defined by recurrent episodes of seizures, which are brief involuntary behavioral alterations caused by paroxysmal intense electrical discharges in the brain. The causes of epilepsy are heterogeneous and include a diverse variety of genetic, metabolic, developmental, traumatic, neoplastic, and vascular etiologies which may present at any time from birth to senescence.
The diagnosis of epilepsy is based on clinical judgment, and may be supported by electroencephalogram, and in some cases, by MRI and blood tests. Seizures can be regarded as symptomatic manifestations of the underlying etiology or pathology. Epilepsy can sometimes be ameliorated by directly treating the underlying etiology, but anticonvulsant drugs, such as phenyloin, gabapentin, lamotrigine, felbamate, and topiramate, and others, which suppress the abnormal electrical discharges and seizures, are the mainstay of conventional treatment (Rho & Sankar, 1999, Epilepsia 40: 1471-1483). Currently available anticonvulsant drugs are effective in suppressing seizures in about 50% of patients, are moderately effective and reduce seizures in another 30-35%, and are ineffective in the remaining 15-20% of patients. The mechanisms of action of the currently-used anticonvulsant drugs are complex and for the most part uncertain, but common general modes of anticonvulsant action include antagonism of sodium ion (Na+) channel function (which modifies repetitive use-dependent neuronal discharge), and modifications in γ-aminobutyric acid and glutamate-mediated synaptic transmission (which favorably alter the balance of excitation and inhibition in neural circuits). These drugs are also effective for treatment of other paroxysmal disorders including syncope, convulsive syncope, migraine, neuropathic pain, and neuropsychiatric conditions with paroxysmal or intermittent behavioral disturbances including bipolar disorders, affective disorders, anxiety disorders, stress disorders, and impulse disorders. In addition, anticonvulsants also provide neuroprotection and reduce infarct size in experimental models of stroke and ischemia.
Neurosurgery is an alternative treatment modality in a small proportion of people for whom drug treatment is ineffective. Patients who continue to have recurring seizures despite treatment with contemporary medications (˜50% of patients) are regarded as medically intractable, and a subset of these patients demonstrate progressive features such as increasing seizure frequency and cognitive decline. Patients with medically intractable epilepsy are usually considered for surgical resective treatment, which may be curative when a localized irritative lesion can be identified. However, certain patients with intractable epilepsy are not candidates for surgical treatment because of the existence of multiple irritative lesions in these patients. This is especially true for children, for whom there is a subset that do not respond well with antiepileptic medications. For such patients, an alternative therapeutic modality is diet, specifically a high-fat diet known as the “ketogenic diet.” In many cases the ketogenic diet may produce effective and sometimes dramatic suppression of seizures and improvements in cognitive function.
The ketogenic diet has been employed for decades in children with epilepsy who have not adequately responded to medical therapy with conventional anticonvulsants (Wilder, 1921, Mayo Clinic Proceedings 2: 307-308; Freeman et al., 1998, Pediatrics 102: 1358-1363). The anticonvulsant action of the diet, which derives calories from high fat intake with very low or no carbohydrates and only adequate protein for growth, is associated with ketosis and production of the ketones β-hydroxybutyrate and acetoacetate. The ketogenic diet can be significantly efficacious and reduce seizures in a substantial subset of patients with severe epilepsy, but understanding of how the diet produces anticonvulsants effects has been limited. One of the remarkable features of the ketogenic diet is that the anticonvulsant effect develops during a period of at least days to weeks after beginning the diet, but is rapidly lost with intake of even very minimal amounts of carbohydrate. Although the diet induces ketosis and generates ketone bodies (inter alia, β-hydroxybutyrate and acetoacetate), in experimental models ketone bodies are not consistently correlated with the anticonvulsant or anti-epileptic effects (Stafstrom & Bough, 2003, Nutritional Neuroscience 6: 67-79; Bough et al., 1999, Developmental Neuroscience 21: 400-406).
Despite its general efficacy, treating patients with the ketogenic diet, particularly children, has several drawbacks. Initiation of the diet typically requires hospitalization for up to one week, and the effects and benefits of the diet (i.e., seizure reduction) are usually not experienced immediately, being delayed from one week to three months from when the diet is started. Maintenance of the diet is difficult, since it requires a balance of nutrients at a particular ratio (usually 3:1 to 4:1 fats to all other nutrients) and intake of even a minimal amount of carbohydrates can eliminate the seizure-relieving benefits of the diet. Side-effects of the diet itself include nausea, vomiting, constipation, depression, sleepiness, lethargy, crankiness, decreased alertness, kidney stones, weight gain, increased serum cholesterol, and acidosis (Ballaban-Gil et al., 1998, Epilepsia 39: 744-748). In addition, the diet has limited effectiveness in adults, and can be even more difficult to implement with children who are allergic to dairy products.
Thus, there is a need in this art to develop methods and compounds for treating epilepsy, particularly medically-intractable epilepsy using alternatives to currently-available anti-epileptic drugs and neurosurgery. There is also a need to develop therapeutically-effective dietary methods other than the ketogenic diet that are easier to implement and maintain and that have fewer side effects and less severe consequences for non-compliance.